Chromosome abnormalities occur with astonishing frequency in humans, with an estimated 10-30% of all fertilized eggs containing structural or numerical abnormalities. Of the different classes of chromosome abnormality, aneuploidy is by far the most common and, clinically, the most important - it is the leading known cause of pregnancy loss and, among those conceptions which survive to term, the leading genetic cause of developmental disabilities. Most aneuploidy results from maternal meiotic errors but, despite their clinical importance, we know very little about chromosome dynamics during human female meiosis, and remain ignorant of the reasons why the process is so error-prone. In the proposed studies, we describe a series of cytological and molecular approaches to study normal and abnormal human female meiosis. Specifically, we will conduct the first systematic analysis of prophase I in the human female, examining the way in which homologous chromosomes pair, synapse and recombine. This will allow us to assess the level of abnormalities in these processes, and to ask whether human chromosomes that are known to be nondisjunction-prone (e.g., 16 and 21) are "predestined" to mal-segregate because of errors in pairing, synapsis or recombination. These studies of fetal oocytes will be partnered with molecular analyses of trisomic fetuses in which the parental and meiotic stage of origin is known, allowing us to determine whether errors in the fetal oocyte are indeed translated into aneuploid conceptions. Cumulatively, these studies represent the first systematic analysis of prophase I in the human female, and the first attempt to link prenatal chromosome behavior with segregation events occurring years later at the time of resumption of meiosis I. Ultimately, our goal is to identify factors responsible for increasing meiotic nondisjunction, and to ask whether we can intervene to decrease the frequency of these abnormalities.